This proposal entails a five-year training program focused on preparing the applicant for an independent career in academic cardiovascular medicine. This project aims to impart the skills and knowledge required for the applicant to achieve his long-term goal of contributing insights into novel molecular pathways that target the exaggerated biological response to vascular injury. The immediate training objectives of the applicant are to master critical experimental techniques, perform coursework that will expand his understanding of advanced molecular biology, develop administrative skills required to function autonomously, and compose a body of work that will enable funding as an independent investigator. Under the guidance of his long-term mentor, Tom Quertermous, and his carefully selected advisory committee of senior investigators, the applicant will have the resources and support to achieve these goals and transition to independence. Project Description: Receptor tyrosine kinases (RTK) are important regulators of cellular signal transduction pathways that play crucial roles in regulating cellular proliferation, differentiation, migration and death;processes integral to the development of atherosclerosis and the response to vascular injury such as venous bypass grafting and balloon angioplasty and stenting. Recently, in order to identify novel aspects of biology and new therapeutic targets we performed comprehensive histological and gene network analysis of human atherosclerosis and in- stent stenosis. Amongst the networks of highly ranked targets was the orphan proto-oncogene RTK Ros1. Evidence for the importance for Ros1 in cardiovascular disease is suggested by studies linking specific Ros1 alleles and heart disease. Allelic variation in ROS1 has been implicated in myocardial infarction, ischemic stroke, in-stent stenosis and hypertension. The causative genes and molecular pathways responsible for the relationship between this genetic variation and the observed cardiovascular risks remain unknown. In this proposal, the investigators seek to elucidate the relationship between the orphan RTK Ros1 and vascular disease. Proposed experiments will build on preliminary work that has implicated a role for RTKs in the response to vascular injury and specifically a role for Ros1 in cell-cycle regulation. Specific aims to be investigated in this proposal will include: (1) determining the role of Ros1 in relevant vascular smooth muscle cell processes, in vitro, (2) characterizing the in vivo effects of Ros1 on atherosclerosis development and (3) characterizing the in vivo effects of Ros1 on the response to vascular injury in models with specific relevance to revascularization in humans with flow limiting atherosclerosis;venous bypass grafting and balloon angioplasty and stenting. These studies are intended to form the foundation of a lifelong career in vascular biology for the applicant. Discoveries made in the course of this proposal are intended to support the stated mission of the National Institutes of Health and provide contributions that will lead to the development of new therapies for patients with cardiovascular disease. PUBLIC HEALTH RELEVANCE: Hardening and narrowing of the arteries, known as atherosclerosis, can lead to such devastating events such as heart attack and stroke. Although revascularization strategies such as bypass surgery and balloon angioplasty with stenting are successful at re-establishing flow in flow limiting atherosclerosis, a significant proportion of patients develop an exaggerated biological response to the injury that occurs as a result of these procedures. Recent studies conducted on human artery tissue extracted at the time of stenting has directed us to a receptor without a known activator, Ros1, which is involved in cell division, growth, movement and death;processes all involved in atherosclerosis. Previous studies looking at the genes involved in atherosclerosis and its related consequences have implicated the gene encoding this receptor, ROS1, in this process. Thus, understanding how this receptor is activated and identifying the pathways that regulate its function may lead to new therapies for blood vessel disorders - currently the leading killer in the Western World.